It is proposed to synthesize a series of new spin-labeled platinum complexes and to utilize these in a series of studies designed to reveal the molecular mechanisms of their actions, not only alone, but also in combination with ionizing radiation. Complexes to be synthesized include the cis and trans isomers of platinum (II) to which piperidine and pyrrolidine nitroxyl biradicals are attached on the amine ligands along with various leaving group ligands such as dichloride, nitrate, and malonate. Analogous platinum (IV) derivatives will also be synthesized and studied. Previous studies on the mechanism of action of antitumor Pt complexes have been hampered by a lack of ability to readily detect the Pt complex during its interaction with cellular constituents. These new spin-labeled complexes are detectable in very small concentrations by EPR spectroscopy. In addition the EPR spectrum contains information which allows quantitation of the bound and unbound fractions of the drug in the same sample and delineation of models of binding of the drug to cellular constituents such as DNA. The biological activity of each complex will be tested. Studies will be carried out in bacterial and mammalian cells in culture to determine the toxicity of each complex at various doses and the ability of each complex to modify the response of the cells to killing by ionizing radiation. The extent and mode or modes of binding of each complex to cellular constituents such as DNA will be studied and related to the degree of toxicity and modification of radiation response. Studies will be done on the identification of the major molecular lesions (e.g. adducts) produced in DNA by the Pt complexes and on their effects on repair processes.